{"doi":"10.1101/2021.03.04.433950","title":"Acyloxyacyl Hydrolase Modulates the Gut Microbiome Through Transcriptional Regulators of Corticotropin-Releasing Factor","abstract":"ABSTRACT Gut microbiome-host interactions play a crucial role in health and disease. Altered gut microbiome composition has been observed in patients with interstitial cystitis/bladder pain syndrome (IC/BPS), a disorder characterized by pelvic pain, voiding dysfunction, and often co-morbid with anxiety/depression. We recently showed that mice deficient for acyloxyacyl hydrolase (AOAH) mimic pelvic pain symptoms and comorbidities of IC/BPS and also exhibit gut dysbiosis. In addition, we previously identified that the conditional knockout (cKO) of two transcriptional regulators of the gene encoding corticotropin-releasing factor, Crf , that are downstream of AOAH, aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor- γ (PPAR γ ), alleviate anxiety/depressive and voiding phenotypes of AOAH-deficient mice. Here, we examined the effects of AhR and PPAR γ in CRF-expressing cells on the dysbiosis of AOAH-deficiency. AOAH-deficient mice with cKO of PPAR γ and AhR/PPAR γ exhibited reduced pelvic allodynia compared to AOAH-deficient mice, suggesting a role for PPAR γ in regulating pelvic pain. 16S rRNA sequencing of fecal stool from female AOAH-deficient mice with a cKO of AhR and/or PPAR γ in CRF-expressing cells identified altered gut microbiota distinct from AOAH-deficient stool. The cKO of AhR and PPAR γ showed improved cecum barrier function in females compared to AOAH-deficient mice, whereas males were primarily affected by PPAR γ , suggesting sex differences in gut responses. Pair-wise comparison of microbiota also suggested sex differences in response to AOAH-deficiency and conditional knockout of AhR and PPAR γ . Our findings suggest that the dysbiosis and leaky gut of AOAH deficiency is mediated by AhR and PPAR γ in CRF-expressing cells and reveal a novel mechanism and therapeutic targets for pelvic pain.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223385,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":824835,"name":"Lizath Aguiniga","orcid":"0000-0002-6641-7541","position":1,"is_corresponding":false},{"id":384950,"name":"Wen‐Bin Yang","orcid":"0000-0002-6497-4176","position":2,"is_corresponding":false},{"id":455895,"name":"Ryan E. Yaggie","orcid":null,"position":3,"is_corresponding":false},{"id":252211,"name":"Bryan A. White","orcid":"0000-0002-9107-1167","position":4,"is_corresponding":false},{"id":441065,"name":"Michael Welge","orcid":null,"position":5,"is_corresponding":false},{"id":173896,"name":"Loretta Auvil","orcid":null,"position":6,"is_corresponding":false},{"id":812243,"name":"Matthew Berry","orcid":"0000-0003-0068-4812","position":7,"is_corresponding":false},{"id":329658,"name":"Colleen Bushell","orcid":"0000-0002-5268-1915","position":8,"is_corresponding":false},{"id":455204,"name":"Anthony J. Schaeffer","orcid":"0000-0002-1324-3517","position":9,"is_corresponding":false},{"id":455205,"name":"David J. Klumpp","orcid":"0000-0002-1237-8364","position":10,"is_corresponding":false},{"id":812758,"name":"Afrida Rahman-Enyart","orcid":null,"position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:11.061295Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}